Project Summary/Abstract Alzheimer's disease (AD) afflicts 6 million people in the USA, and the number of AD patients will double by 2050 if no cure is identified. The clinical dementia of AD is coupled to a distinct pathology, with ?-amyloid plaques, neurofibrillary tangles, and synaptic loss. Synapses are essential for cognitive function, and their loss is well established as the major structural correlate of cognitive impairment in AD. An early event in AD pathogenesis, synaptic failure is detectable in individuals with the prodromal stage of MCI. Positron Emission Tomography (PET) imaging is increasingly employed in studies of AD, using tracers for glucose metabolism, ?- amyloid, and neurofibrillary tangles. However, currently, there are no PET radioligands that directly image synaptic density in vivo, which would be of high utility in studies of AD as well as in monitoring potential therapies. One suitable molecular target for a synaptic density imaging agent is the synaptic vesicle glycoprotein 2 (SV2), an essential vesicle membrane protein, with one of its isoforms, SV2A, ubiquitously expressed in virtually all synapses. We recently developed 11C-UCB-J as a promising radioligand for quantitative measurement of SV2A with PET. In our pilot first-in-human SV2A PET studies in healthy subjects, we found that 11C-UCB-J has the potential to be an excellent PET tracer for quantitative imaging of SV2A in the human brain, and can act as a general-purpose tool for measuring synaptic vesicle density. We propose to apply 11C-UCB-J with human imaging studies in AD. In Aim 1, we will quantify SV2A using bolus/infusion delivery on the High Resolution Research Tomography (HRRT) and examine SV2A density in AD compared to healthy controls (HC). We hypothesize that 11C-UCB-J will reveal decreased SV2A binding in the AD brain with a pattern that may differ from the cortical regions previously validated for 18F-FDG. All subjects will also be evaluated for amyloid status and the effect of overall amyloid status on SV2A binding will be determined. In Aim 2, we will compare group and individual differences in SV2A density to differences in glucose metabolism measured with 18F-FDG. Regional patterns of deficits will be compared to HC for the 2 tracers. We hypothesize that the magnitude of reduction in specific binding of 11C-UCB-J in AD compared to HC will be greater than that found with 18F-FDG. Further, we will correlate the magnitude of reduction in synaptic density and glucose metabolism with neuropsychological test performance. Aim 3 compares the group and individual differences in amyloid distribution from 11C-PIB to SV2A-PET as well as FDG-PET, with the expectation that patterns of synaptic loss produced by 11C-UCB-J will differ from that of amyloid PET, particularly in the earlier phases of the AD spectrum. In summary, this project will take the first critical steps to validating a novel imaging biomarker of synaptic density for studies in AD and other neuropsychiatric disorders.